SUMMARY:
Participants in the large CASCADE cohort who started antiretroviral
therapy (ART) with a CD4 cell count in the 350-500 cells/mm3
range -- in accordance with current U.S. treatment guidelines
-- had a reduced likelihood of death than those who deferred
until later, investigators reported at the XVIII International
AIDS Conference last week in Vienna. Starting above 500 cells/mm3,
however, did not reduce the risk of progression to AIDS or
death in this analysis.

A growing
body of evidence suggests that early antiretroviral
therapy, before the immune system sustains significant damage, leads
to better outcomes, including protection against opportunistic
illness, non-AIDS conditions such as cardiovascular disease and
cognitive impairment, and overall mortality. On the other hand, however,
starting early could cause problems related to long-term drug-related
toxicities and resistance.

A large
randomized study known as START is just getting underway, and a recent
smaller analysis from Haiti offered some of the first data from a randomized
trial indicating that earlier ART is beneficial. Most evidence on this
question, however, has come from observational cohort studies.

As described
by Joseph Eron and fellow investigators, the CASCADE Collaboration is
an ongoing natural history study of HIV seroconverters from more than
2 dozen clinical cohorts in Europe, Australia, and Canada followed since
the start of the combination ART era in the late 1990s.

The CASCADE
"When to Start" analysis looked at outcomes according to whether
participants started or deferred treatment. The study included 9455
patients enrolled between January 1996 and May 2009. At the time of
enrollment they were at least 6 months past seroconversion, did not
have an AIDS diagnosis, and had not yet started ART.

Most participants
(78%) were men (56% men who have sex with men). The average age at the
time of seroconversion was 30 years and the estimated duration of infection
was 1.3 years. People who started treatment had better prognosis in
some respects (including less likely to have a history of injection
drug use or to be coinfected with hepatitis B or C), but poorer prognosis
in others (including higher viral load, shorter duration of infection,
and slightly lower average CD4 cell count).

Participants
were analyzed in 161 sequential nested cohorts of people enrolled during
a single month. The researchers compared those who started ART (defined
as any three-drug antiretroviral regimen) versus those who deferred
for that month, looking at how many developed an AIDS-defining illness
or died from any cause. Participants who remained alive could join the
next monthly cohort, so some were members of multiple cohorts. They
were followed for about 5 years on average for a total 52,268 person-years
of data.

Researchers
described the study as "intent-to-treat in spirit." Outcomes
among people who started therapy and those who deferred during a given
month (regardless of what they did later) could not be directly compared
since participants were not randomly assigned to one strategy or the
other.

A limitation
of the analysis is that it did not include serious non-AIDS-defining
conditions -- such as cardiovascular, kidney, and liver disease -- that
occur more often among HIV positive compared with HIV negative people
in the ART era and contribute to shorter life expectancy. It also did
not account for treatment interruptions after starting ART or therapy
that did not produce full viral suppression.

Participants
were divided into 5 categories according to CD4 cell count: 0-49 cells/mm3
(n = 183), 50-199 cells/mm3 (n = 1521), 200-349 cells/mm3 (n = 4459),
350-499 cells/mm3 (n = 5527), and 500-799 cells/mm3 (n = 5162). People
with more than 800 cells/mm3 were not included in the analysis because
they contributed too few events for a meaningful statistical analysis.

Results

Overall,
812 people (8.6%) progressed to AIDS during the study period.

A
total of 544 participants (5.8%) died during the study.

Benefits
of starting ART were clearly evident among people with lower CD4
counts, but less so at higher levels:

0-49
cells/mm3: 55 events per 1000 person-years (PY) among those
who started ART vs 193 per 1000 PY among those who deferred;
adjusted hazard ratio (HR) 0.32, or 68% reduction in risk;

Analysis
of 3-year cumulative event rates emphasized the differential benefit
according to CD4 count, including calculation of the number of patients
who would need to start treatment to prevent 1 case of AIDS or death:

0-49
cells/mm3: 17% cumulative risk for those who started ART vs
47% for those who deferred; number needed to treat = 3;

For death alone, the respective numbers need to treat to prevent
1 death were 6, 14, 74, 71, and 239 patients, respectively.

The researchers
concluded that starting antiretroviral therapy with a CD4 count <
500 cells/mm3 "appears to reduce risk compared to deferring at
baseline."

At CD4
counts of 350-499 cells/mm3 and above, however, "absolute risk
[was] very low in [the] short term (1 year)," and at CD4 counts
of 500-700 cells/mm3, there was "no apparent benefit to [ART] initiation
for the larger population of patients with CD4s in this range."

These
findings support current U.S.
treatment guidelines recommending ART initiation when CD4 count
falls below 500 cells/mm3. Given that the analysis left out non-AIDS
conditions, however, the issue of whether treatment is beneficial above
this level remains unresolved.

In the
words of session moderator Sharon Walmsley from the University of Toronto,
"We know to start [ART] early, but how early we still don't know."